The present invention relates to multi-unit, delayed, sustained-release pharmaceutical preparations, and more particularly, to microparticles formed of a water-soluble core drug coated with a single, hydratable diffusion barrier which allows a prolonged delayed and sustained release drug delivery.
As is well known, the maximum time of effectiveness in many pharmaceutical preparations, particularly those containing a drug such as aspirin, acetaminophen, indomethacin, propranolol hydrochloride, dextromethorphan, etc. is only a few hours because of biological modification and/or elimination of the medication in the body. Consequently, repeated doses must be taken at frequent intervals to obtain long term therapeutic levels of drug. Furthermore, these drugs usually dissolve readily in the digestive juices and the total dosage is immediately fed into the blood stream. After high initial peak concentrations, the level of drug in the blood stream constantly decreases because of the biological elimination, so there is little or no therapeutic effect at the end of the period between doses. As a result, the therapeutic effect fluctuates between doses corresponding to the peaks and valleys in the level of drug in the blood.
Many attempts have been made to develop timed-release pharmaceutical preparations which provide a more constant level of the drug in the blood over several hours.
One common approach is to microencapsulate aspirin, for example, with a capsule wall material which provides a slower dissolution rate than free aspirin. The early work in that regard is represented by U.S. Pat. Nos. 3,155,590; 3,341,416; 3,488,418; and 3,531,418. Those patents, among others, disclose dispersing particles of aspirin in a hot cyclohexane solution containing ethyl cellulose and then introducing a phase-separation inducing agent, such as butyl rubber or polyethylene. Upon cooling, the aspirin particles become coated with ethyl cellulose. The coated particles are then admixed with tableting excipients and formed into dosage-sized tablets. When ingested, the tablets disintegrate rapidly and the individual particles of encapsulated aspirin are dispersed in the stomach. The gastric juices slowly diffuse through the capsule walls, dissolve the aspirin, and the dissolved aspirin slowly diffuses or leaches out through the capsule walls into the body. Although the resultant blood level content is sustained to a measurable extent, the aspirin is diffused into the body rapidly enough so there is an initially high blood level content which decreases quite rapidly within a few hours.
As a result, efforts have been made to adjust the rate of dissolution and, thus, control the timing of sustained drug release. See, for example, Peters, U.S. Pat. No. 3,492,397 where the dissolution rate is said to be controlled by adjusting the wax/ethyl cellulose ratio of the applied spray coating, and Mehta, U.S. Pat. No. 4,752,470 where the controlled release characteristics for indomethacin are varied depending on the ratio of ethyl cellulose to hydroxypropyl cellulose in the coating. See also U.S. Pat. Nos. 4,205,060 and 3,488,418 where it is indicated that the rate of dissolution of various drugs can be controlled by varying the thickness of the coating applied to those drugs.
Another method for providing an encapsulated pharmaceutical composition is discussed in published European patent Application No. 77,956, published May 4, 1983. EPO Publication No. 77,956 discloses the use of microcapsules containing a coated core material such as pharmaceutical compounds and foodstuffs. The coating is applied by dispersing the core material into a solution containing ethyl cellulose as the wall-forming material. A phase separation of the ethyl cellulose from the dispersion of core material is carried out by cooling the dispersion. During this cooling, an enteric polymer material is incorporated into the ethyl cellulose coating walls by adding the enteric polymer material with stirring while the ethyl cellulose is still in the "gel" state. The enteric polymer material thus added penetrates and is dispersed into the coating walls. When the microcapsules are administered, the release of the active compound does not generally occur in the stomach. However, the enteric polymer material is easily dissolved in the intestinal tract, thereby making the microcapsules porous. The porosity of the microcapsules promotes the rapid release of the active compound in the intestinal tract.
A similar approach is found in Japanese Patent Publication No. 12614/81, published Mar. 23, 1981. Japanese Publication No. 12614/81 discloses an enteric protective coating composition which will not readily dissolve in acidic gastric juices, but rapidly (within minutes) dissolves at the pH found in the intestines. The enteric coating is an aqueous dispersion of, for example, hydroxy propyl methyl cellulose phthalate, a gelling agent such as diacetin, and hydroxy propyl methyl cellulose. See, also, Japanese Patent Publication No. 11687/81, published Mar. 16, 1981, which uses hydroxy propyl methyl cellulose phthalate as an enteric coating.
The systems described in the EPO and Japanese publications are essentially "delayed" release mechanisms. There is a delay of medicament release in the stomach, but once the coated medicament reaches the intestines, the release of medication is rapid. There is no sustained release of medication in the intestines.
Still other systems for sustained-release pharmaceutical preparations are known. For example, Fukui et al, U.S. Pat. No. 4,772,475, relate to a controlled-release pharmaceutical formulation comprising a granular core mixed with water-insoluble polymers such as acrylic acid polymers and copolymers, and cellulose derivatives which allows gradual release of the drug in the gastrointestinal tract.
Mughal et al, U.S. Pat. No. 4,524,060, relate to a sustained-release pharmaceutical composition comprising a mixture of micronised indoramin, a water-channeling agent such as microcrystalline cellulose, and a wetting agent comprising anionic surfactants. The mixture is coated with an enteric coating such as hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate and acrylic resins, or a sustained-release coating such as natural waxes or mixtures of polymers, such as ethyl cellulose, which is permeable to gastro-intestinal juices.
Barry et al, U.S. Pat. No. 4,900,558 disclose a pharmaceutical formulation providing sustained release over a 12-hour period comprising a drug core containing ibuprofen and microcrystalline cellulose, and a coating covering the core comprising a water-insoluble but water-swellable acrylic polymer and a water-soluble hydroxylated cellulose derivative.
In addition, Published EPO application 212745 discloses sustained-release drug particles containing an ibuprofen drug core, an inner coating of an enteric material such as acrylic polymers and copolymers, and an outer coating such as methacrylic acid polymers and copolymers which are insoluble at any pH and act as a diffusion barrier for the drug.
While the above-mentioned references provide a more constant rate of drug release, in some instances, it is desirable to mix the delayed sustained-release preparation with an immediate release drug to obtain a biphasic drug release profile. For example, Radebaugh et al, U.S. Pat. No. 4,968,509, disclose a sustained-release acetaminophen formulation formed by mixing acetaminophen with hydroxyethyl cellulose and a wicking agent such as microcrystalline cellulose, and then adding a povidone granulating agent. The sustained-release formulation may be part of a multi-layered tablet containing an immediate-release layer of acetaminophen to quickly elevate and then maintain the blood levels of acetaminophen.
Reference is also made to Eichel, U.S. Pat. No. 5,026,559, which discloses a delayed and sustained-release pharmaceutical preparation comprising a multi-walled coated drug having an inner wall microencapsular enteric coating, such as polymethacrylic acid/acrylic acid copolymer or cellulose acetate phthalate, a solid acid either incorporated in the enteric layer or layered over the enteric layer, and an outer wall microencapsulated control coating, such as polymethacrylic acid ester copolymer or ethyl cellulose. The solid acid delays drug release by maintaining the enteric polymer in an impermeable state until the acid diffuses out of the drug or is neutralized. The multi-walled coated drug is admixed with an uncoated drug having immediate therapeutic properties upon dissolution in the stomach.
However, many of the multi-walled preparations described above do not provide prolonged delayed release of the drug prior to initiation of sustained release, which is important when biphasic release profiles are desired.
Accordingly, the need exists for a delayed, sustained-release pharmaceutical preparation which provides a longer delay of drug dissolution which would provide greater flexibility in designing sustained-release profiles for a wide variety of drugs, provides constant blood concentration levels, is simply and economically produced, and has the advantages of a multi-units formulation.